The retinal pigment epithelium (RPE) is a specialized epithelium at the back of the eye that carries out a variety of functions essential for visual health. Recent studies have advanced our molecular understanding of one of the major functions of the RPE; phagocytosis of spent photoreceptor outer segments (POS). Notably, a mechanical link, formed between apical integrins bound to extracellular POS and the intracellular actomyosin cytoskeleton, is proposed to drive the internalization of POS. The process may involve a (...) “nibbling” action, as an initial step, to sever outer segment tips. These insights have led us to hypothesize an “integrin adhesome‐like” network, atypically assembled at apical membrane RPE‐POS contacts. I propose that this hypothetical network orchestrates the complex membrane remodeling events required for particle internalization. Therefore, its analysis and characterization will likely lead to a more comprehensive understanding of the molecular mechanisms that control POS phagocytosis. (shrink)

The limbus is a narrow band of tissue that encircles the cornea, the transparent ‘window’ into the eye. The outermost layer of the cornea is the epithelium, which is necessary for clear vision. The limbus acts as a ‘reservoir’ for limbal stem cells which maintain and regenerate the corneal epithelium. It also functions as a barrier to the conjunctiva and its blood vessels. Limbal stem cell deficiency is a general term for diseases which are characterised by the impairment (...) of the limbus, limbal stem cells and their ability to replenish the corneal epithelium through proliferation and differentiation. Consequently, sufferers experience chronic pain and progressive blindness. This paper will highlight the salient milestones of limbal stem cell biology and potential future treatments for limbal stem cell deficiency. (shrink)

Clonal studies of adult chimaeric mouse epithelium have demonstrated the monoclonal composition of crypts of Lieberkühn(1). In neonatal life, however, polyclonal crypts have been found, indicating that crypts are of polyclonal origin(2). We here relate these findings to studies of mosaic tissues which have addressed the question whether solid tumours are of monoclonal or polyclonal origin (ref. 3 for review, 4). The issues has so far remained unresolved because the expected frequencies of polyclonal tumours, given polyclonal origins, have not (...) previously been estimated. A general approach for the calculation of such expected values is suggested. The consistent reports of tumours with polyclonal components suggest that autocrine or paracrine mechanisms play an important role during tumorigenesis. (shrink)

In the 4 1/2 to 5 days between fertilization and implantation, the mouse conceptus must gain the abilities to implant and produce an embryo. Each of these is the sole developmental responsibility of one of two cell types forming the blastocyst, trophectoderm and inner cell mass (ICM), respectively. Trophectoderm is a polarized transporting epithelium while the ICM is an aggregate of non‐epithelial pluripotent stem cells. These two cell types originate from the division of polar blastomeres when their cleavage furrows (...) parallel their apical surfaces. Blastomeres polarize in response to asymmetric cell–cell contact, and understanding the mechanism of this induction is regarded as the key to understanding the origin of trophectoderm and ICM. Here we propose a model based on transcellular ion current loops for the induction of cell polarity during the development of the first epithelium, trophectoderm. (shrink)

The retina pigment epithelium (RPE) is a highly specialised epithelium that serves as a multifunctional and indispensable component of the vertebrate eye. Although a great deal of attention has been paid to its transdifferentiation capabilities and its ancillary functions in neural retina development, little is known about the molecular mechanisms that specify the RPE itself. Recent advances in our understanding of the genetic network that controls the progressive specification of the eye anlage in vertebrates have provided some of (...) the initial cues to the mechanisms responsible for RPE patterning. Here, we have outlined many recent findings that suggest that a limited number of transcription factors, including Otx2, Mitf and Pax6 and a few signalling cascades, are the elements required for the onset of RPE specification in vertebrates. Furthermore, using this information and the data available on the specification of the pigmented cells of primitive chordates, we have ventured some hypotheses on the origin of RPE cells during evolution. BioEssays 26:766–777, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

We review recent progress in the stem cell biology of the respiratory system, and discuss its scientific and translational ramifications. Several studies have defined novel stem cells in postnatal lung and airways and implicated their roles in tissue homeostasis and repair. In addition, significant advances in the generation of respiratory epithelium from pluripotent stem cells (PSCs) now provide a novel and powerful platform for understanding lung development, modeling pulmonary diseases, and implementing drug screening. Finally, breakthroughs have been made in (...) the generation of decellularized lung matrices that can serve as a scaffold for repopulation with respiratory cells derived from either postnatal or PSCs. These studies are a critical step forward towards the still distant goal of stem cell‐based regenerative medicine for diseases of lung and airways. (shrink)

We hypothesize that aspects of animal multicellularity originated before the divergence of metazoans from fungi and social amoebae. Polarized epithelial tissues are a defining feature of metazoans and contribute to the diversity of animal body plans. The recent finding of a polarized epithelium in the non‐metazoan social amoeba Dictyostelium discoideum demonstrates that epithelial tissue is not a unique feature of metazoans, and challenges the traditional paradigm that multicellularity evolved independently in social amoebae and metazoans. An alternative view, presented here, (...) is that the common ancestor of social amoebae, fungi, and animals spent a portion of its life cycle in a multicellular state and possessed molecular machinery necessary for forming an epithelial tissue. Some descendants of this ancestor retained multicellularity, while others reverted to unicellularity. This hypothesis makes testable predictions regarding tissue organization in close relatives of metazoans and provides a novel conceptual framework for studies of early animal evolution.Editor's suggested further reading in BioEssays Searching for Eve: Basal metazoans and the evolution of multicellular complexity Abstract. (shrink)

Notch is a mechanosensitive receptor that requires direct cell–cell contact for its activation. Both the strength and the range of notch signaling depend on the size and geometry of the contact sites between cells. These properties of cell–cell contacts in turn depend on cell shape and polarity. At the molecular level, the E3 ubiquitin ligase Neuralized links receptor activation with epithelial cell remodeling. Neur regulates the endocytosis of the Notch ligand Delta, hence Notch activation. It also targets the apical polarity (...) protein Stardust to promote the endocytosis of the Crumbs complex, thereby contributing to epithelium remodeling. Here, we review the interplay between Notch signaling and cell polarity and discuss the possible significance of linking Notch signaling with epithelial cell polarity via a common regulator. Notch receptor activation depends on direct cell–cell contacts that in turn depends on cell shape and cellular polarity. The size and geometry of cell–cell contacts have an impact on the strength and range of signaling. The E3 ubiquitin ligase Neuralized regulates the endocytosis and signaling activity of Delta. The activity of Neuralized is tightly regulated during development. Neuralized also modulates epithelial cell polarity by targeting the apical polarity protein Stardust and by promoting the endocytosis of Crumbs. Thus, the cell-specific expression of Neuralized couples Notch receptor activation with cell polarity regulation in epithelia. (shrink)

Trichoplax adhaerens is more simply organized than any other living metazoan. This tiny marine animal looks like a irregular “hairy plate” (“tricho plax”) with a simple upper and lower epithelium and some loose cells in between. After its original description by F.E. Schulze 1883, it attracted particular attention as a potential candidate representing the basic and ancestral state of metazoan organization. The lack of any kind of symmetry, organs, nerve cells, muscle cells, basal lamina and extracellular matrix originally left (...) little doubt about the basal position of T. adhaerens. Nevertheless, the interest of zoologists and evolutionary biologists suddenly vanished for more than half a century when Trichoplax was claimed to be an aberrant hydrozoan planula larva. Recently, Trichoplax has been rediscovered as a key species for unraveling early metazoan evolution. For example, research on regulatory genes and whole genome sequencing promise insights into the genetics underlying the origin and development of basal metazoan phyla. Trichoplax offers unique potential for understanding the minimal requirements of metazoan animal organization. BioEssays 27:1294–1302, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

The chronologic age classically used in demography is often unable to give useful information about which exact stage in development or aging processes has reached an organism. Hence, we propose here to explain in some applications for what reason the chronologic age fails in explaining totally the observed state of an organism, which leads to propose a new notion, the biological age. This biological age is essentially determined by the number of divisions before the Hayflick’s limit the tissue or mitochondrion (...) in a critical organ (in the sense where its loss causes the death of the whole organism) has already used for its development and adult phases. We give a precise definition of the biological age of an organ based on the Hayflick’s limit of its cells and we introduce a desynchronization index (the cell entropy) for some critical tissues or membranes, which are mainly skin, intestinal endothelium, alveoli epithelium and mitochondrial inner membrane. In these actively metabolising interface tissues or membranes, there is a rapid turnover of cells, of their cytoplasmic constituents such as proteins, and of membrane lipids. The boundaries corresponding to these tissues, cells or membranes have vital functions of interface with the environment (protection, homeothermy, nutrition and respiration) and have a rapid turnover (the total cell renewal time is in mice equal to 3 weeks for the skin, 1.5 day for the intestine, 4 months for the alveolae and 11 days for mitochondrial inner membrane) conditioning their biological age. The biological age of a tissue is made of two major components: (1) first, its embryonic age based on the distance (in number of divisions) between the birth date of its first differentiated cell and the time until it reaches its final boundary at the end of its development and (2) second, its adult age whose complement until its death is just the lapse of time made of the sum of remaining cell cycle durations authorized by its Hayflick’s limit. From this definition, we calculate the global biological lifespan of an organism and revisit notions like demographic survival curves, duration and synchrony of cell cycles, living boundaries from proto-cells to organs, and embryonic and adult phases duration. (shrink)

This article considers the role of the adult epithelial stem cell, with particular reference to the intestinal epithelial stem cell. Although the potential of adult stem cells has been revealed in a number of recent publications, the organization and control of the stem cell hierarchy in epithelial tissues is still not fully understood. The intestinal epithelium is an excellent model in which to study such hierarchies, having a distinctive polarity and high rate of cell proliferation and migration. Studies on (...) the small intestinal crypt provide insight into the characteristics of the stem cells in normal and regenerating circumstances and demonstrate why a thorough understanding of these cells is an essential pre‐requisite for stem cell based therapeutic approaches. BioEssays 24:91–98, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Isthmin‐1 (Ism1) was first described to be syn‐expressed with Fgf8 in Xenopus. However, its biological role has not been elucidated until recent years. Despite of accumulated evidence that Ism1 participates in angiogenesis, tumor invasion, macrophage apoptosis, and glucose metabolism, the cognate receptors for Ism1 remain largely unknown.Ism1deficiency in mice results in renal agenesis (RA) with a transient loss ofGdnftranscription and impaired mesenchyme condensation at E11.5. Ism1 binds to and activates Integrin α8β1 to positively regulate Gdnf/Ret signaling, thus promoting mesenchyme condensation (...) and ureteric epithelium branching morphogenesis. Here, we propose the hypothesis underlying the mechanism by which Ism1 regulates branching morphogenesis during early kidney development. (shrink)

Planar cell polarity, the polarization of cells within the plane of the epithelium, orthogonal to the apical‐basal axis, is essential for a growing list of developmental events, and – over the last 15 years – has evolved from a little‐studied curiosity in Drosophila to the subject of a substantial research enterprise. In that time, it has been recognized that two molecular systems are responsible for polarization of most tissues: Both the “core” Frizzled system and the “global” Fat/Dachsous/Four‐jointed system produce (...) molecular asymmetry within cells, and contribute to morphological polarization. In this review, we discuss recent findings on the molecular mechanism that links “global” directional signals with local coordinated polarity. (shrink)

Recent studies support a model in which the progeny of SOX9+ epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal‐to‐proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9+ progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9+ progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and differentiation are integrated (...) with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9+ cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9+ progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made. (shrink)

The Cambrian explosion is characterized by the sudden outburst of organized animal plans, which occurred circa 530 M years ago. Around that time, many forms of animal life appeared, including several which have since disappeared. There is no general consensus about “why” this happened, and why it had any form of suddenness. However, all organized animal plans share a common feature: they are triploblastic, i.e., composed of 3 layers of tissue, endoderm, ectoderm and mesoderm. I show here that, within simple (...) hypotheses, the formation of the mesoderm has intrinsically a physical exponential dynamics, leading rapidly to triploblastism, and eventually, to animal formation. A novel physico-mathematical framework including epithelium-mesenchyme transition, visco-elastic constitutive equations, and conservation laws, is presented which allows one to describe gastrulation as a self-wetting phenomenon of a soft solid onto itself. This phenomenon couples differentiation and migration during gastrulation, and leads in a closed form to an exponential scaling law for the formation of the mesoderm. Therefore, the Cambrian explosion might have started, actually, by a true visco-elastic “explosion”: the exponential run-away of mesenchymal cells. (shrink)

Skin is one of the most thoroughly studied epithelia and can be used as a model for transcriptional control of epithelial differentiation. In particular, the stages of epidermal development and differentiation from a simple epithelium are well characterized. Temporal gene expression during development can be used to assign roles for transcription factors in epidermal differentiation. Approaches to understanding transcriptional regulation in epidermis include extensive promoter analysis and expression studies, in some cases coupled to functional studies. This work has not (...) produced any consensus about the importance of any particular factor or class of factors in epidermal specification. There is, as yet, nothing similar to the myo D family of tissue‐specific and cell‐type determining factors in epidermis. These studies, however, have revealed much about control of the differentiation process in epidermis. Most recently, there has been a suggestion that epithelial transcription can be influenced directly by the status of the adhesion complexes at the cell surface, providing a direct link between one of the distinguishing features of the epithelial state and gene transcription. (shrink)

An early embryo becomes a blastula at the moment that its constituent cells become organised into a simple epithelium. Epithelial folding and compartmentation are essential elements of animal development. All the different cell types ‐ epithelial and other ones ‐ of which a differentiated organism consists differ in their plasmamembrane‐cytoskeletal complex but they are assumed to have an identical genome. The hypothesis is put forward that, perhaps, the basic mechanism underlying differentiation can be defined as the generation of cells (...) which have an identical genome but which differ in their plasmamembrane‐cytoskeletal complex and which, because of these differences, can engage in differential protein synthesis‐physiology. (shrink)

The polarized organization of epithelial cells is expressed in many ways including the morphology of the cell surface or cytocortex, the molecular composition of membrane domains and the distribution of cytoplasmic organelles. The differentiation of mouse trophectoderm is described with particular attention given to the maturation of the endocytic system in an attempt to define how the complex assembly of an epithelium may be generated.

Long non‐coding RNAs (lncRNAs) have recently gained increasing attention because of their crucial roles in gene regulatory processes. Functional studies using mammalian skin as a model system have revealed their role in controlling normal tissue homeostasis as well as the transition to a diseased state. Here, we describe how lncRNAs regulate differentiation to preserve an undifferentiated epidermal progenitor compartment, and to maintain a functional skin permeability barrier. Furthermore, we will reflect on recent work analyzing the impact of lncRNAs on the (...) progression from normal epithelium to the development of skin disorders and cancer. (shrink)

The integrity of epithelia depends largely on specialised adhesive structures, the adherens junctions. Several of the components required for building these structures are highly conserved between vertebrates and insects (e.g. E‐cadherin and α‐ and β‐catenin), while others have so far been found only in invertebrates (e.g. crumbs). Two recent papers(1,2) show that the Drosophila E‐cadherin is encoded by the gene shotgun. Phenotypic analyses of shotgun as well as armadillo (β‐catenin) and crumbs mutants provide new insights into the mechanisms by which (...) adherens junctions are built and, further, show that the requirement for E‐cadherin largely depends on the morphogenetic activity of an epithelium. (shrink)

The Krüppel‐like factors (KLFs) comprise a family of evolutionarily conserved zinc finger transcription factors that regulate numerous biological processes including proliferation, differentiation, development and apoptosis. KLF4 and KLF5 are two closely related members of this family and are both highly expressed in epithelial tissues. In the intestinal epithelium, KLF4 is expressed in terminally differentiated epithelial cells at the villus borders of the mucosa and inhibits cell growth, while KLF5 is expressed in proliferating epithelial cells at the base of the (...) intestinal crypts and promotes cell growth. KLF4 and KLF5 respond to a myriad of external stress stimuli and are likely involved in restoring cellular homeostasis following exposure to stressors. Confirming their importance in maintaining tissue integrity, KLF4 and KLF5 are both dysregulated in various types of cancer. Here we review the recent advances in defining the physiological and pathobiological roles of KLF4 and KLF5, focusing on their functions in the intestinal epithelium. BioEssays 29:549–557, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

A theoretical model is presented for pattern formation in an epithelium. The epithelial model consists of a thin, incompressible, viscoelastic membrane on an elastic foundation (substrate), with the component cells assumed to have active contractile properties similar to those of smooth muscle. The analysis includes the effects of large strains and material nonlinearity, and the governing equations were solved using finite differences. Deformation patterns form when the cells activate while lying on the descending limb of their total (active + (...) passive) stress-stretch curve. Various one-dimensional and two-dimensional simulations illustrate the effects of spatial and temporal variations in passive stiffness, as well as the effects of foundation stiffness and stretch activation. The model can be used to examine the mechanical aspects of pattern formation in morphogenetic processes such as angiogenesis and myocardial trabeculation. (shrink)

The ectoplasmic specialization (ES) is a testis‐specific, actin‐based hybrid anchoring and tight junction. It is confined to the interface between Sertoli cells at the blood–testis barrier, known as the basal ES, as well as between Sertoli cells and developing spermatids designated the apical ES. The ES shares features of adherens junctions, tight junctions and focal contacts. By adopting the best features of each junction type, this hybrid nature of ES facilitates the extensive junction‐restructuring events in the seminiferous epithelium during (...) spermatogenesis. For instance, the α6β1‐integrin–laminin 333 complex, which is usually limited to the cell–matrix interface in other epithelia to facilitate cell movement, is a putative apical ES constituent. Furthermore, JAM‐C and CAR, two tight junction integral membrane proteins, are also components of apical ES involving in spermatid orientation. We discuss herein the mechanisms that maintain the cross‐talk between ES and blood–testis barrier to facilitate cell movement and orientation in the seminiferous epithelium. BioEssays 29: 36–48, 2007. © 2006 Wiley Periodicals, Inc. (shrink)

A fundamental aspect of biological systems is their spatial organization. In development, regeneration and repair, directional signals are necessary for the proper placement of the components of the organism. Likewise, pathogens that invade other organisms rely on directional signals to target vulnerable areas. It is widely understood that chemical gradients are important directional signals in living systems. Less well recognized are electrical fields, which can also provide directional information. Small, steady electrical fields can directly guide cell movement and growth and (...) can generate chemical gradients of charged macromolecules against the leveling action of diffusion. At the site of a lesion in an ion‐transporting epithelium, for example, a substantial electrical field is instantly generated and may extend over many cell diameters. There are numerous other situations in which relatively long‐range electrical fields have been shown to exist naturally. Recently, there has been substantial progress in identifying specific processes that are controlled, to some extent, by these endogenous electrical fields. This review highlights these recent data and discusses possible mechanisms by which the fields might affect biological processes. BioEssays 25:759–766, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The mechanisms by which cells become polarised in the plane of an epithelium have been studied in Drosophila for many years. Work has focussed on two key questions: firstly, how individual cells adopt a defined polarity, and secondly how the polarity of each cell within a tissue is aligned with its neighbours. It has been established that asymmetric subcellular localisation of a number of polarity proteins is an essential mechanism underlying polarisation of single cells. The process by which this (...) polarity is coordinated between cells however is less well understood, but is thought to involve gradients of activity of the atypical cadherins Dachsous and Fat. Subsequently, this long‐range polarity signal is refined by local cell–cell interactions involving the transmembrane molecules Frizzled, Strabismus and Flamingo. The role of these factors in coordinating polarity will be discussed. BioEssays 27:1218–1227, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Shortly after implantation the embryonic lineage transforms from a coherent ball of cells into polarized cup shaped epithelium. Recently we elucidated a previously unknown apoptosis‐independent morphogenic event that reorganizes the pluripotent lineage. Polarization cues from the surrounding basement membrane rearrange the epiblast into a polarized rosette‐like structure, where subsequently a central lumen is established. Thus, we provided a new model revising the current concept of apoptosis‐dependent epiblast morphogenesis. Cell death however has to be tightly regulated during embryogenesis to ensure (...) developmental success. Here, we follow the stages of early mouse development and take a glimpse at the critical signaling and morphogenic events that determine cells destiny and reshape the embryonic lineage. (shrink)

Recent technical improvements, such as 3D microscopy imaging, have shown the necessity of studying 3D biological tissue architecture during carcinogenesis. In the present paper a computer simulation model is developed allowing the visualization of the microscopic biological tissue architecture during the development of metaplastic and dysplastic lesions.The static part of the model allows the simulation of the normal, metaplastic and dysplastic architecture of an external epithelium. This model is associated to a knowledge base which contains only data on the (...) nasal epithelium. The latter has been well studied by numerous authors and its lesional states are well known. An inference engine allows the initialization of the static model parameters. A statistical comparison between simulated epithelia and real epithelia is achieved by adjusting the parameter values during the simulation. (shrink)

Drosophila imaginal discs (appendage primordia) have proved invaluable for deciphering cellular and molecular mechanisms of animal development. By combining the accessibility of the discs with the genetic tractability of the fruit fly, researchers have discovered key mechanisms of growth control, pattern formation and long‐range signaling. One of the principal experimental attractions of discs is their anatomical simplicity — they have long been considered to be cellular monolayers. During larval stages, however, the growing discs are 2‐sided sacs composed of a columnar (...) epithelium on one side and a squamous ‘peripodial’ epithelium on the other. Recent studies suggest important roles for peripodial epithelia in processes previously assumed to be confined to columnar cell monolayers. BioEssays 23:691–697, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Planar cell polarity (PCP) refers to the polarization of a field of cells within the plane of a cell sheet. This form of polarization is required for diverse cellular processes in vertebrates, including convergent extension (CE), the establishment of PCP in epithelial tissues and ciliogenesis. Perhaps the most distinct example of vertebrate PCP is the uniform orientation of stereociliary bundles at the apices of sensory hair cells in the mammalian auditory sensory organ. The establishment of PCP in the mammalian cochlea (...) occurs concurrently with CE in this ciliated epithelium, therefore linking three cellular processes regulated by the vertebrate PCP pathway in the same tissue and emerging as a model system for dissecting PCP signaling. This review summarizes the morphogenesis of this model system to assist the interpretation of the emerging data and proposes molecular mechanisms underlying PCP signaling in vertebrates. BioEssays 29: 120–132, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Human skin produces numerous neurohormones and neuropeptides. Recent evidence has shown that the neuroendocrine regulation of human skin biology also extends to keratins, the major structural components of epithelial cells. For example, thyrotropin‐releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1‐ligands profoundly modulate human keratin gene and protein expression in human epidermis and/or hair follicle epithelium in situ. Since selected keratins are now understood to exert important regulatory functions beyond mechanical stability, we argue that neuroendocrine pathways of keratin regulation (...) are important for maintaining skin and hair follicle homeostasis. This invites innovative neuroendocrine therapeutic interventions for skin disorders characterized by abnormal keratin expression, ranging from psoriasis to genodermatoses, and for promoting skin wound healing and hair growth. This strategy can be probed in simple, but instructive and readily available human skin and hair follicle organ culture assays as ideal models for exploring this new neuroendocrine frontier in translational epithelial biology. (shrink)

Airway mucin secretion is important pathophysiologically and as a model of polarized epithelial regulated exocytosis. We find the trafficking protein, SNAP23, selectively expressed in secretory cells compared with ciliated and basal cells of airway epithelium by immunohistochemistry and FACS, suggesting that SNAP23 functions in regulated but not constitutive epithelial secretion. Heterozygous SNAP23 deletant mutant mice show spontaneous accumulation of intracellular mucin, indicating a defect in baseline secretion. However mucins are released from perfused tracheas of mutant and wild-type mice at (...) the same rate, suggesting that increased intracellular stores balance reduced release efficiency to yield a fully compensated baseline steady state. In contrast, acute stimulated release of intracellular mucin from mutant mice is impaired whether measured by a static imaging assay 5 min after exposure to the secretagogue ATP or by kinetic analysis of mucins released from perfused tracheas during the first 10 min of ATP exposure. Together, these data indicate that increased intracellular stores cannot fully compensate for the defect in release efficiency during intense stimulation. The lungs of mutant mice develop normally and clear bacteria and instilled polystyrene beads comparable to WT mice, consistent with these functions depending on baseline secretion that is fully compensated. (shrink)

Recent studies uncovered critical roles of the adhesion protein E‐cadherin in health and disease. Global inactivation of Cdh1, the gene encoding E‐cadherin in mice, results in early embryonic lethality due to an inability to form the trophectodermal epithelium. To unravel E‐cadherin's functions beyond development, numerous mouse lines with tissue‐specific disruption of Cdh1 have been generated. The consequences of E‐cadherin loss showed great variability depending on the tissue in question, ranging from nearly undetectable changes to a complete loss of tissue (...) structure and function. This review focuses on these studies and discusses how they provided important insights into E‐cadherin's role in cell adhesion, proliferation and differentiation, and its consequences for biological processes as epithelial‐to‐mesenchymal transition, vascularization, and carcinogenesis. Lastly, we present some perspectives and possible approaches for future research. (shrink)

In the seminiferous tubule of the mammalian testis, one type A1 spermatogonium (diploid, 2n) divides and differentiates into 256 spermatozoa (haploid, n) during spermatogenesis. To complete spermatogenesis and produce ∼150 × 106 spermatozoa each day in a healthy man, germ cells must migrate progressively across the seminiferous epithelium yet remain attach to the nourishing Sertoli cells. This active cell migration process involves precisely controlled restructuring events at the tight (TJ) and anchoring junctions at the cell–cell interface. While the hormonal (...) events that regulate spermatogenesis by follicle‐stimulating hormone and testosterone from the pituitary gland and Leydig cells, respectively, are known, less is known about the mechanism(s) that regulates junction restructuring during germ cell movement in the seminiferous epithelium. The relative position of tight (TJs) and anchoring junctions in the testis is of interest. Sertoli cell TJs that constitute the blood–testis barrier (BTB) are present side by side with anchoring junctions and are adjacent to the basement membrane. This intimate physical association with the TJs, the anchoring junctions and the basement membrane (a modified form of extracellular matrix, ECM) suggests a role for the ECM in the junction dynamics of the testis. Indeed, evidence is accumulating that ECM proteins are crucial to Sertoli cell TJ dynamics. In this review, we discuss the pivotal role of tumor necrosis factor α (TNFα) on BTB dynamics via its effects on the homeostasis of ECM proteins. In addition, discussion will also be focused on the novel findings regarding the role of non‐basement‐membrane‐associated ECM proteins and components of focal adhesion (a cell–matrix anchoring junction type) in the regulation of junction dynamics in the testis. BioEssays 26:978–992, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Large numbers of cells with unique neuronal specificity are generated during development of the central nervous system of animals. Here we discuss the events that generate cell diversity during early development of the ventral nerve cord of different arthropod groups. Neural precursors are generated in a spatial array in the epithelium of each hemisegment over a period of time. Spatial cues within the epithelium are thought to evolve as embryogenesis proceeds. This spatiotemporal information might generate diversity among the (...) neural precursors in all arthropod groups, although the mechanisms regulating the positioning of individual precursors have diverged. However, distinct strategies for the generation of neuronal diversity have evolved in the different arthropod lineages that appear to correlate with specific modes of ontogenesis. We hypothesize that an evolutionary trend towards reduced cell numbers and possibly rapid embryogenesis in insects has culminated in the appearance of stereotyped neuroblast lineages. BioEssays 27:874–883, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Unraveling molecular and functional heterogeneity of niche cells within the developing endoderm could resolve mechanisms of tissue formation and maturation. Here, we discuss current unknowns in molecular mechanisms underlying key developmental events in pancreatic islet and intestinal epithelial formation. Recent breakthroughs in single‐cell and spatial transcriptomics, paralleled with functional studies in vitro, reveal that specialized mesenchymal subtypes drive the formation and maturation of pancreatic endocrine cells and islets via local interactions with epithelium, neurons, and microvessels. Analogous to this, distinct (...) intestinal niche cells regulate both epithelial development and homeostasis throughout life. We propose how this knowledge can be used to progress research in the human context using pluripotent stem cell‐derived multilineage organoids. Overall, understanding the interactions between the multitude of microenvironmental cells and how they drive tissue development and function could help us make more therapeutically relevant in vitro models. (shrink)

During gestation, fetomaternal exchange occurs in the villous tree (labyrinth) of the placenta. Development of this structure depends on tightly coordinated cellular processes of branching morphogenesis and differentiation of specialized trophoblast cells. The basal chorionic trophoblast (BCT) cell layer that localizes next to the chorioallantoic interface is of critical importance for labyrinth morphogenesis in rodents. Gcm1‐positive cell clusters within this layer initiate branching morphogenesis thereby guiding allantoic fetal blood vessels towards maternal blood sinuses. Later these cells differentiate and contribute to (...) the syncytiotrophoblast of the fetomaternal barrier. Additional cells within the BCT layer sustain continued morphogenesis, possibly through a repopulating progenitor population. Several mouse mutants highlight the importance of a structurally intact BCT epithelium, and a growing number of studies addresses its patterning and epithelial architecture. Here, we review and discuss emerging concepts in labyrinth development focussing on the biology of the BCT cell layer. (shrink)

Essentially we show recent data to shed new light on the thorny controversy of how teeth arose in evolution. Essentially we show (a) how teeth can form equally from any epithelium, be it endoderm, ectoderm or a combination of the two and (b) that the gene expression programs of oral versus pharyngeal teeth are remarkably similar. Classic theories suggest that (i) skin denticles evolved first and odontode‐inductive surface ectoderm merged inside the oral cavity to form teeth (the ‘outside‐in’ hypothesis) (...) or that (ii) patterned odontodes evolved first from endoderm deep inside the pharyngeal cavity (the ‘inside‐out’ hypothesis). We propose a new perspective that views odontodes as structures sharing a deep molecular homology, united by sets of co‐expressed genes defining a competent thickened epithelium and a collaborative neural crest‐derived ectomesenchyme. Simply put, odontodes develop ‘inside and out’, wherever and whenever these co‐expressed gene sets signal to one another. Our perspective complements the classic theories and highlights an agenda for specific experimental manipulations in model and non‐model organisms. (shrink)

It is often suggested that during development the brain barriers are immature. This argument stems from teleological interpretations and experimental observations of the high protein concentrations in fetal cerebrospinal fluid (CSF) and decreases in apparent permeability of passive markers during development. We argue that the developmental blood–CSF barrier restricts the passage of lipid‐insoluble molecules by the same mechanism as in the adult (tight junctions) rendering the paracellular pathway an unlikely route of entry. Instead, we suggest that both protein and passive (...) markers are transferred across the epithelium through a transcellular route. We propose that changes in volume of distribution can largely explain the decrease in apparent permeability for passive markers and that developmentally regulated cellular transfer explains changes in CSF protein concentrations. The blood–CSF tight junctions are functionally mature from very early in development, and it appears that transfer from blood into embryonic brain occurs predominately via CSF rather than the vasculature. BioEssays 30:237–248, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Recent work by Fernández‐Sánchez and coworkers examining the impact of applied pressure on the malignant phenotype of murine colon tissue in vivo revealed that mechanical perturbations can drive malignant behavior in genetically normal cells. Their findings build upon an existing understanding of how the mechanical cues experienced by cells within a tissue become progressively modified as the tissue transforms. Using magnetically stimulated ultra‐magnetic liposomes to mimic tumor growth ‐induced solid stress, Fernández‐Sánchez and coworkers were able to stimulate β‐catenin to promote (...) the cancerous behavior of both a normal and genetically modified colon epithelium. In this perspective, we discuss their findings in the context of what is currently known regarding the role of the mechanical landscape in cancer progression and β‐catenin as a mechanotransducer. We review data that suggest that mechanically regulated activation of β‐catenin fosters development of a malignant phenotype in tissue and predict that mechanical cues may contribute to tumor heterogeneity. (shrink)

Neutrophil transepithelial migration is a central component of many inflammatory diseases of the gastrointestinal, respiratory and urinary tracts, and correlates with disease symptoms. In vitro modeling with polarized intestinal epithelial monolayers has shown that neutrophil transepithelial migration can influence crucial epithelial functions, ranging from barrier maintenance to electrolyte secretion. Studies have also demonstrated a dynamic involvement of the epithelium in modulating neutrophil transepithelial migration. Characterization of the molecular interactions between neutrophils and epithelial cells has revealed that transepithelial migration is (...) dependent on the neutrophil β2 integrin CD11b/CD18, and does not appear to involve adhesive interactions with the selectins or intercellular adhesion molecule‐1. Recent studies have implicated another transmembrane glycoprotein, CD47, as a crucial component of the transepithelial migration response. While the precise function of CD47 is not known, current evidence suggests that CD47‐dependent events occur after CD11b/CD18‐mediated neutrophil adhesion to the epithelium. This review will highlight key features of the current understanding of the molecular events important in neutrophil migration across epithelial surfaces. (shrink)

Epithelia are the first organized tissues that appear during development. In many animal embryos, early divisions give rise to a polarized monolayer, the primary epithelium, rather than a random aggregate of cells. Here, we review the mechanisms by which cells organize into primary epithelia in various developmental contexts. We discuss how cells acquire polarity while undergoing early divisions. We describe cases where oriented divisions constrain cell arrangement to monolayers including organization on top of yolk surfaces. We finally discuss how (...) epithelia emerge in embryos from animals that branched early during evolution and provide examples of epithelia‐like arrangements encountered in single‐celled eukaryotes. Although divergent and context‐dependent mechanisms give rise to primary epithelia, here we trace the unifying principles underlying their formation. (shrink)

The polar orientation of cells within a tissue is an intensively studied research area in animal cells. The term planar polarity refers to the common polar arrangement of cells within the plane of an epithelium. In plants, the subcellular analysis of tissue polarity has been limited by the lack of appropriate markers. Recently, research on plant tissue polarity has come of age. Advances are based on studies of Arabidopsis patterning, cell polarity and auxin transport mutants employing the coordinated, polar (...) localization of auxin transporters and the planar polarity of root epidermal hairs as markers. These approaches have revealed auxin transport and response, vesicular trafficking, membrane sterol and cytoskeletal requirements of tissue polarity. This review summarizes recent progress in research on vascular tissue and planar epidermal polarity in the Arabidopsis root and compares it to findings on planar polarity in animals and cell polarity in yeast. BioEssays 26:719–729, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Tetrapods have two distinct nasal chemosensory systems, the main olfactory system and the vomeronasal system (VNS). Defined by certain morphological components, the main olfactory system is present in all groups of vertebrates, while the VNS is found only in tetrapods. Previous attempts to identify a VNS precursor in teleost fish were limited by functional and morphological characters that could not clearly distinguish between homologous and analogous systems. In the past decade, several genes that specifically function in the VNS have been (...) discovered. Here we first describe recent evolutionary studies of mammalian VNS‐specific genes. We then review evidence showing the presence and tissue‐specific expression of the VNS‐specific genes in teleosts, as well as co‐expression patterns of these genes in specific regions of the teleost olfactory epithelium. We propose that a VNS precursor exists in teleosts and that its evolutionary origin predated the separation between teleosts and tetrapods. BioEssays 28: 709–718, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

During development of the anterior eye segment, cells that originate from the surface epithelium or the neuroepithelium need to interact with mesenchymal cells, which predominantly originate from the neural crest. Failures of proper interaction result in a complex of developmental disorders such Peters' anomaly, Axenfeld–Rieger's syndrome or aniridia. Here we review the role of transcription factors that have been identified to be involved in the coordination of anterior eye development. Among these factors is PAX6, which is active in both (...) epithelial and mesenchymal cells during ocular development, albeit at different doses and times. We propose that PAX6 is a key element that synchronizes the complex interaction of cell types of different origin, which are all needed for proper morphogenesis of the anterior eye. We discuss several molecular mechanisms that might explain the effects of haploinsufficiency of PAX6 and other transcription factors, and the broad variation of the resulting phenotypes. BioEssays 26:374–386, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

It may be possible, one day, to use gene therapy to treat diseases whose genetic defects have been discerned. Because many genes responsible for inherited eye disorders within the retina have been identified, diseases of the eye are prime candidates for this form of therapy. The eye also has the advantage of being highly accessible with altered immunological properties, important considerations for easy delivery of virus and avoidance of systemic immune responses. Currently, adenovirus, adeno‐associated virus and lentivirus have been used (...) to successfully transfer genetic material to retinal pigment epithelium and photoreceptor cells. By harnessing therapeutic genes to these viruses, researchers have been able to demonstrate rescue in rodent models of retinitis pigmentosa, providing evidence that this form of therapy can be effective in delaying photoreceptor cell death. Future challenges include confirming therapeutic effects in animal models with eyes more anatomically similar to those of humans and demonstrating long‐term rescue with minimal toxicity. BioEssays 23:662–668, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

The external surfaces of the human body, as well as its internal organs, constantly experience different kinds of mechanical stimulations. For example, tubular epithelial cells of the kidney are continuously exposed to a variety of mechanical forces, such as fluid flow shear stress within the lumen of th nephron. The majority of epithelial cells along the nephron, except intercalated cells, possess a primary cilium, an organelle projecting from the cell's apical surface into the luminal space. Despite its discovery over 100 (...) years ago, the primary cilium's function continued to elude researchers for many decades. However, recent studies indicate that renal cilia have a sensory function. Studies on polycystic kidney disease (PKD) have identified many of the molecular players, which should help solve the mystery of how the renal cilium senses fluid flow. In this review, we will summarize the recent breakthroughs in PKD research and discuss the role(s) of th polycystin signaling complex in mediating mechanosensory function by the primary cilium of renal epithelium as well as of the embryonic node. BioEssays 26:844–856, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Late lung development comprises the formation of the terminal sac followed by the subdivision of the terminal sac by septa into alveoli and results in the formation of the gas‐exchange surface of the lung. This developmentally regulated process involves a complex epithelium–mesenchyme interaction via evolutionarily conserved molecular signaling pathways. In addition, there is a continuous process of vascular growth and development. Currently there are large gaps in our understanding of the molecular mechanisms involved in the formation of the gas‐exchange (...) surface. In this review, we attempt to integrate and reconcile the morphologic features in late lung development with what is known about the molecular basis for these processes. We describe the formation of the terminal sac and the subsequent formation of the septa, which divide the terminal sac into alveoli, in terms of the classically described developmental stages of induction, morphogenesis and differentiation. We believe that evolutionarily conserved pathways regulate this process and that morphogen gradients are likely to be a central mechanism. In addition, we highlight the importance of the molecular mechanisms involved in the simultaneous development of the vascular bed and its importance in the late development of the lungs. BioEssays 24:1052–1059, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

In order to survive, the developing conceptus must interrupt the normal ovarian cycle of the mother and extend the production of progesterone by the corpus luteum. An unusual Type 1 interferon (IFN), related structurally to the IFN–α molecule and produced in massive amounts for only a few days by the first epithelium (trophectoderm) of the preimplantation conceptus, has been implicated as the antiluteolytic agent in sheep and cattle. IFN‐a therapy during this critical period can also improve pregnancy success in (...) sheep. It remains unclear, however, whether the trophoblast IFN have specialized biological properties or whether they are unique merely in the timing, magnitude and site of their expression. (shrink)

Epithelia can be defined morphologically as tissues that line surfaces, and ultrastructurally with reference to their cells' apico‐basal polarity and possession of specific cell‐cell junctions. Defining the epithelial phenotype at a molecular level is more problematic ‐ while it is easy to name proteins (e.g. keratins) expressed by a “typical” epithelium, no known molecules are expressed by every epithelium but by no other tissues. Cells can differentiate to and from the epithelial state as part of normal development, as (...) a response to disease or when manipulated in culture. Many factors (matrix components, adhesion molecules, growth factors, transcription factors) have been identified that can trigger these transitions of phenotype in specific cases, but to date no general master regulators of the epithelial state have been found. The epithelial state may therefore be controlled by multiple regulatory genes so that there is no single molecule responsible for all of the diverse types of epithelium that exist in higher animals. (shrink)

The embryonic vertebrate face is composed of similarly sized buds of neural crest‐derived mesenchyme encased in epithelium. These buds or facial prominences grow and fuse together to give the postnatal morphology characteristic of each species. Here we review the role of neural crest cells and foregut endoderm in differentiating facial features. We relate the developing facial prominences to the skeletal structure of the face and review the signals and genes that have been shown to play an important role in (...) facial morphogenesis. We also examine two experiments one at the genetic level and one at the signal level in which transformation of facial prominences and subsequent change of jaw identity was induced. We propose that signals such as retinoids and BMPs and downstream transcription factors such as Distal‐less related genes specify jaw identity. BioEssays 25:554–568, 2003. © 2003 Wiley Periodicals, Inc. (shrink)